The management of epilepsy in pregnancy

Good seizure control can be achieved with anti-epileptic drug (AED) therapy in approximately two thirds of patients, maximising the chance of leading a normal, seizure-free life. However, AEDs can have adverse effects including teratogenesis.

Women with epilepsy who are planning a pregnancy face a dilemma. To remain seizure free, or to keep seizures under reasonable control, they need to continue to take drugs which can have potentially harmful effects on the developing foetus in utero, and which may also have an adverse influence on postnatal development.

At least 15 per cent of women currently stop taking their AED in early pregnancy, risking seizures that include severe withdrawal seizures with catastrophic results.

Confidential enquiries into maternal deaths in the UK report an excess of indirect deaths in women with epilepsy.

PREGNANCY RISKS

Women with epilepsy feel they lack information on most of the issues important to them, including teratogenesis.

Past studies of older AEDs, including phenobarbitone, phenytoin, carbamazepine and sodium valproate, have shown a two- to threefold increase in the background major malformation rate, with a further increase in risk if more than one AED is used in combination as polytherapy.

The risk of teratogenesis from untreated epilepsy appears to be low.

Information and counselling has been difficult because absolute and relative risks vary from study to study.

Studies are often retrospective and may examine only small selected populations.

Data have been limited to the older AEDs, some of which are no longer widely used.

TREATMENT CHOICE

Treatments for epilepsy that have emerged over the past 15 years have provided more choice and sometimes greater efficacy.

For example, lamotrigine is one of the newer AEDs that is now widely prescribed in the UK as a 'first choice' because of its relatively low side-effect profile. Counselling its use in women of child-bearing age has been difficult because of the lack of human pregnancy data on the newer AEDs.

To address this need a prospective observational register of pregnant women with epilepsy was set up in 1996 by Dr Jim Morrow, a neurologist from Belfast, who now co-ordinates the UK Epilepsy and Pregnancy Register.

The aim of the register is to obtain statistically significant data on pregnancy outcome in women with epilepsy, particularly with regard to major congenital malformations (MCM) identified within three months after delivery.

It is designed to attract the registration of large numbers of pregnancies with the collection of minimal but robust and essential data. Data collected at registration includes details of the epilepsy and its treatment. The patient's GP is then contacted three months after the delivery for pregnancy and pregnancy outcome data.

The study group recognises that this does have limitations when considering possible confounding factors such as seizure frequency and smoking.

Patients can self register or consent to be registered by their doctor, nurse, or midwife.

RESULTS

The first results of this on-going study were published online in September 2005.

Analysis of the first 3,607 pregnancies and outcomes have shown that the AEDs most frequently prescribed as monotherapy in women who consented to be included on the register between 1996 and 2005 are carbamazepine, sodium valproate and lamotrigine.

The results are generally encouraging for most women, with epilepsy with good pregnancy outcomes reported in almost 96 per cent of the study group.

As with previous studies, the risk from monotherapy is significantly lower, at 3.7 per cent, compared with a polytherapy risk of 6 per cent.

Although the number of unexposed pregnancies was relatively small at 239, the risk of a MCM in this group was 3.5 per cent.

MCM RISK

Orofacial clefts, congenital heart defects, neural tube defects, hypospadias, skeletal and gastrointestinal abnormalities were all reported, some in combination in a few infants.

When individual AEDs were examined, differences emerged. The relative risk of a MCM was lowest with carbamazepine and highest with sodium valproate.

The difference between these two drugs was highly significant with a risk for valproate of 6.2 per cent and for carbamazepine of 2.2 per cent (p<0.001).

Results for lamotrigine monotherapy were encouraging, with an overall monotherapy risk of 3.2 per cent.

The dose of AED may also be important. A positive dose response for MCMs was noted for lamotrigine with a MCM rate of 5.4 per cent for total daily doses of more than 200mg (p=0.006). There was a similar trend with sodium valproate.

For pregnancies exposed to more than 1,000mg of valproate a day, the MCM rate was 9.1 per cent. The MCM rate in pregnancies exposed to doses of 1,000mg or less of valproate was 5.1 per cent, similar to those exposed to 200mg or more of lamotrigine.

COMBINATION THERAPY

Specific combinations of AEDs also appear important. Combinations which included sodium valproate carried the highest risk at 9 per cent; 18 per cent of the polytherapy group were pregnancies exposed to a combination of valproate and lamotrigine, which was associated with an MCM rate of 9.6 per cent.

Recently there has been a tendency to prescribe lamotrigine in preference to sodium valproate to teenagers and women of child-bearing age. Lamotrigine is less efficacious in controlling seizures in idiopathic generalised epilepsies, such as juvenile myoclonic epilepsy.

Data on newer AEDs in use - for example, topiramate, levetiracetam, gabapentin, pregabalin, and zonisamide - are more limited because of the smaller numbers of monotherapy pregnancies ascertained to date.

PREGNANCY OUTCOME

The overall results are encouraging, with a good outcome for the majority of pregnancies.

Sodium valproate does appear to be the more teratogenic of commonly prescribed AEDs in the UK, particularly when used in combination with other AEDs.

It is regarded as the most efficacious treatment for idiopathic generalised epilepsies - such as juvenile myoclonic epilepsy which commonly presents in adolescence.

Also, the observation that monotherapy with lower doses of valproate or higher doses of lamotrigine carry similar risks of MCM should be noted.